Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/79276
Title: dissectHMMER: a HMMER-based score dissection framework that statistically evaluates fold-critical sequence segments for domain fold similarity
Authors: Wong, Wing-Cheong
Yap, Choon-Kong
Eisenhaber, Birgit
Eisenhaber, Frank
Issue Date: 2015
Source: Wong, W.-C., Yap, C.-K., Eisenhaber, B., & Eisenhaber, F. (2015). dissectHMMER: a HMMER-based score dissection framework that statistically evaluates fold-critical sequence segments for domain fold similarity. Biology Direct, 10(39).
Series/Report no.: Biology Direct
Abstract: Background: Annotation transfer for function and structure within the sequence homology concept essentially requires protein sequence similarity for the secondary structural blocks forming the fold of a protein. A simplistic similarity approach in the case of non-globular segments (coiled coils, low complexity regions, transmembrane regions, long loops, etc.) is not justified and a pertinent source for mistaken homologies. The latter is either due to positional sequence conservation as a result of a very simple, physically induced pattern or integral sequence properties that are critical for function. Furthermore, against the backdrop that the number of well-studied proteins continues to grow at a slow rate, it necessitates for a search methodology to dive deeper into the sequence similarity space to connect the unknown sequences to the well-studied ones, albeit more distant, for biological function postulations. Results: Based on our previous work of dissecting the hidden markov model (HMMER) based similarity score into fold-critical and the non-globular contributions to improve homology inference, we propose a framework-dissectHMMER, that identifies more fold-related domain hits from standard HMMER searches. Subsequent statistical stratification of the fold-related hits into cohorts of functionally-related domains allows for the function postulation of the query sequence. Briefly, the technical problems as to how to recognize non-globular parts in the domain model, resolve contradictory HMMER2/HMMER3 results and evaluate fold-related domain hits for homology, are addressed in this work. The framework is benchmarked against a set of SCOP-to-Pfam domain models. Despite being a sequence-to-profile method, dissectHMMER performs favorably against a profile-to-profile based method-HHsuite/HHsearch. Examples of function annotation using dissectHMMER, including the function discovery of an uncharacterized membrane protein Q9K8K1_BACHD (WP_010899149.1) as a lactose/H+ symporter, are presented. Finally, dissectHMMER webserver is made publicly available at http://dissecthmmer.bii.a-star.edu.sg. Conclusions: The proposed framework-dissectHMMER, is faithful to the original inception of the sequence homology concept while improving upon the existing HMMER search tool through the rescue of statistically evaluated false-negative yet fold-related domain hits to the query sequence. Overall, this translates into an opportunity for any novel protein sequence to be functionally characterized. Reviewers: This article was reviewed by Masanori Arita, Shamil Sunyaev and L. Aravind.
URI: https://hdl.handle.net/10356/79276
http://hdl.handle.net/10220/38714
ISSN: 1745-6150
DOI: 10.1186/s13062-015-0068-3
Rights: © 2015 Wong et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:SCSE Journal Articles

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